JP6023875B2 - Ophthalmic viscoelastic device - Google Patents

Description

  The present invention relates to an ophthalmic viscoelastic device comprising at least one viscoelastic polymer. The invention further relates to a method for producing an ophthalmic viscoelastic device comprising at least one viscoelastic polymer.

  Cataract is a common disease in the elderly, and gradually becomes cloudy in the lens. This clouding of the lens causes vision loss. To restore vision, cataract surgery must be performed. The standard method for producing a lens capsule that removes the opaque nucleus of the lens and inserts an artificial intraocular lens (IOL) is so-called lens emulsification using a device that generates ultrasonic vibrations. The aligned cubic cell endothelial layer, particularly in the Descemet's membrane of the corneal endothelium, may be affected by this iatrogenic treatment.

The endothelial cell layer maintains corneal transparency by regulating the net ion flux from the stroma to the aqueous humor that keeps the stroma relatively dehydrated. These cell densities in elderly cataract patients are approximately 2600 cells / mm ² . Corneal endothelial cells cannot divide and if their density drops to approximately 500 cells / mm ² , there is a risk of corneal edema due to stromal dehydration and therefore no more transparency can be maintained. This is one of the most serious complications common in early lens emulsification techniques. The delicate endothelial cell layer can be damaged, for example, by mechanical trauma from the instrument, impact by lens fragments or biochemical and mechanical action of the irrigation solution.

  Immediately prior to lens emulsification, the anterior chamber is usually filled with a so-called ophthalmic viscoelastic device (OVD) to protect the endothelium. Viscoelastic OVDs are used as surgical aids to protect intraocular tissues (eg, corneal endothelium during lens emulsification) and as space maintainers (eg, to retain the anterior chamber of the eye) Used, for example, to facilitate intraocular manipulation so that a controlled capsulotomy is performed.

  Ophthalmic viscoelastic devices are mostly aqueous solutions containing viscoelastic polymers such as hyaluronic acid, hydroxypropylmethylcellulose, chondroitin sulfate or mixtures thereof. Viscoelastic compositions are distinguished by the molecular weight of the polysaccharide dissolved in the solution, the concentration of the polysaccharide and the viscosity of the solution. OVD is well tolerated after slight exposure to intraocular tissue.

  However, a further side effect in the lens emulsification process is the generation of free radicals that can affect, inter alia, the endothelial cells inside the cornea. This monolayer is essential for maintaining the transparency of the cornea. Free radicals, particularly hydroxyl radicals, are generated by ultrasonic oscillation, and acoustic cavitation is induced to cause separation of water vapor. These free radicals have been said to be a significant factor in endothelial damage due to the induction of apoptosis after cataract extraction.

  By adding scavengers (scavengers) to the OVD, such radical concentrations can be lowered, thereby helping to protect the ocular tissue. Further use of scavengers buffers the amount of oxygen free radicals, thereby increasing their protective performance, during cataract surgery, in addition to OVD viscoelasticity, appropriate pH value and appropriate osmolality. Reduced loss of endothelial cells is promoted.

  Patent Document 1 discloses a viscoelastic composition containing an aqueous solution of a viscoelastic polymer. The viscoelastic composition contains a polyol such as tris (hydroxymethyl) aminomethane and sorbitol as a scavenger.

  However, these scavengers can diffuse from the OVD into the eye tissue or fluid and cause unwanted side effects. Diffusion into body fluids can cause unwanted local or overall pharmacological effects, for example, by binding to receptor targets. In addition, problems arise when hydrophobic scavengers with relatively low water solubility are used because they precipitate out of solution and accumulate in ocular tissue.

US Patent Application Publication No. 2005 / 0215516A1

  The object of the present invention is to improve an ophthalmic viscoelastic device of the type mentioned at the outset in order to be simpler and safer in application. It is a further object of the present invention to provide a method for manufacturing such an ophthalmic viscoelastic device.

  According to the present invention, these objects are achieved by an ophthalmic viscoelastic device having the features of claim 1 and a method for producing an ophthalmic viscoelastic device having the features of claim 11. Advantageous developments of the invention are specified in the respective dependent claims, in which case the advantageous development of the ophthalmic viscoelastic device is regarded as the advantageous development of the method and vice versa. .

In an ophthalmic viscoelastic device (OVD) according to the first aspect of the invention comprising at least one viscoelastic polymer, at least one viscoelastic polymer is covalently bonded to at least one phenolic compound. In this case, within the scope of the present invention, the chemical compound is a phenolic compound belonging to the class of chemical compounds containing at least one hydroxyl group (—OH) bonded or linked directly to an aromatic hydrocarbon group according to the general formula Can be understood by the term

The simplest class is phenol, also called carboxylic acid (C ₆ H ₅ OH).

  The covalent bond or association of the phenolic compound to the viscoelastic polymer provides various advantages. First, phenolic compounds exhibit high antioxidant activity, trap free radicals, and reduce the concentration of reactive oxygen species in the patient's eye. A phenol compound can form a stable radical by delocalizing an unpaired electron to an aromatic electron system. The amount of free radicals produced during lens emulsification can be confirmed by electron spin resonance (ESR) spectroscopy. An in vitro device to test this radical scavenging effect has been described by Cameron et al. (Identification of free radicals produced during lens emulsification, JCRC 2001; 27: 463-470). Based on the results, the amount and concentration of the phenolic compound in the OVD can be adjusted. Furthermore, by immobilizing a phenol compound to OVD, the radical scavenging activity is limited to a region where free radicals are generated during lens emulsification. Still further, the phenolic compound is covalently bonded to at least one viscoelastic polymer to ensure that the scavenger does not diffuse into adjacent tissues during use of OVD. Further, since condensation and precipitation can be prevented by adhesion to the viscoelastic polymer, a low water-soluble phenol scavenger compound can be used. In the simplest configuration, OVD consists of a solution of a single viscoelastic polymer to which a phenolic compound is covalently bonded. Alternatively, an ophthalmic viscoelastic device, sometimes referred to as an ophthalmic composition, can include a plurality of different viscoelastic polymers and / or additives. Alternatively, two or more different phenolic compounds can be covalently attached to the viscoelastic polymer.

  In an advantageous development of the invention, at least one phenolic compound is bound to the viscoelastic polymer directly and / or via a spacer. This allows the phenolic compound to be particularly easily adapted and covalently bound to the current reactive group of the polymer. The use of spacers is advantageous, for example, if the reactive group of the phenolic compound cannot be coupled to the reactive group of the corresponding polymer, or only within the scope of a multistage reaction. In addition, the use of spacers is advantageous when the scavenger behavior of the phenolic compound is undesirably affected by covalent bonding to the polymer. Also, the use of spacers can affect the viscoelastic properties of the polymer as required.

  In a further advantageous development of the invention, the viscoelastic polymer comprises a polysaccharide. In this case, the ophthalmic viscoelastic device has a particularly high biocompatibility. Suitably the polysaccharide is a glycosaminoglycan.

  In a further advantageous development of the invention, the polysaccharide is a cellulose, a cellulose ether having methyl and / or ethyl and / or propyl groups, in particular hydroxypropylmethylcellulose, hydroxyethylmethylcellulose and / or methylcellulose, glycosaminoglycan, in particular Hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, keratan sulfate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan and / or mixtures thereof It is. In this case, in particular, the viscoelastic properties of OVD can be adapted to the intended use and used in an optimal manner. Here, basically, OVD contains two or more of the same type of polysaccharide, which differ only in the type and / or molecular ratio of the covalently bonded phenolic compound.

  In a further advantageous development of the invention, at least one viscoelastic polymer is covalently bonded with at least one dye. In this case, within the scope of the present invention, the chemical compound absorbs light in the wavelength range of about 380 nm to about 800 nm that is visible to the human eye and preferably does not exhibit fluorescence or phosphorescence. It will be understood that the dye contains a molecular structure. Covalent bonding of the dye with at least one viscoelastic polysaccharide ensures that the dye diffuses into adjacent tissues and is not unnecessarily stained during use of the ophthalmic viscoelastic device or composition. be able to. Furthermore, unlike fluorescent dyes such as fluorescein and rhodamine, it is not necessary to irradiate the ophthalmic viscoelastic device with UV light for visualization. This allows the ophthalmic viscoelastic device to be handled substantially more easily. Furthermore, perhaps the tissue is not at risk of being damaged by high energy UV light. In addition, the user, e.g., a surgeon, can recognize even small marks without additional aids such as UV lamps by virtue of the integral coloration of the ophthalmic viscoelastic device, so that the ophthalmic viscoelastic device according to the invention can be recognized. The use of an elastic device becomes substantially simpler and safer, for example, within the scope of ophthalmic surgery. In the simplest configuration, an ophthalmic viscoelastic device consists of a viscoelastic polymer to which one specific dye is covalently bonded. Ophthalmic viscoelastic devices are also composed of two or more different viscoelastic polymers, with one particular dye covalently bonded to one or more polymers. Alternatively, two or more different dyes can be covalently attached to the viscoelastic polymer to provide a particular color.

  In a further advantageous development of the invention, the dye comprises a reactive dye from the group of phenolic compounds and / or modified and / or unmodified aminoanthracenedione and / or modified and / or unmodified nitrophenyldiazenylbenzenamine. That is, the phenol compound itself is assumed to be a dye. This allows phenolic compounds to be advantageous for both radical scavenging and use as dyes, while ophthalmic viscoelastic devices can be manufactured especially at low cost while providing particularly safe and easy handling To do. Alternatively or additionally, at least one viscoelastic polymer is replaced with at least one reactive dye from the group of polymers and modified and / or unmodified aminoanthracenedione and / or modified and / or unmodified nitrophenyldiazenylbenzenamine Can be obtained by reaction with. By using aminoanthracenedione or aminoanthracenedione derivatives and / or nitrophenyldiazenylbenzenamine or nitrophenyldiazenylbenzenamine derivatives as dyes to covalently bond to the polymer, the color of the viscoelastic polymer and the ophthalmic viscoelastic device is visible. It offers the advantage of being particularly adjustable over almost the entire range. Furthermore, these two dyes or dye groups are characterized by fast cleaning and light weight. Therefore, the handling of the ophthalmic viscoelastic device is particularly simple and safe and has high storage stability.

Here, at least one polymer can be obtained by reaction with at least one reactive dye of the general formula (I).

In the general formula (I), at least one of the substituents R _{1 to} R ₈ is an amino group, and the remaining substituents R _{1 to} R ₈ different from the amino group are hydrogen, halogen, C ₁ -C _{4 alkyl,} C 1 -C _{4 alkoxy,} C 1 -C ₄ - alkoxy _-C 1 -C ₄ - _alkyl, C 1 -C ₄ - alkyl _-C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkoxy - C ₁ -C ₄ -alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyramide, sulfonate, (aminophenyl) -N-alkylacetamide, (aminophenylsulfonyl) alkyl sulfate, alkylbenzenesulfonamide, tri ( Alkyl) benzenamine, hydroxy, (alkylsulfonyl) benzeneamine, (alkenylsulfonyl) base Select from Zen'amin, and / or at least two adjacent substituents _{R X, R x + 1 (} x = 1~3 and / or 5-7) are 3-, 4-, 5-, 6- or 7-membered (Member) monocyclic or heterocyclic radicals are formed, which may be unsaturated or aromatic. Here, all stereoisomers, racemic mixtures and positional isomers are considered to be included. The dyes of general formula (I) can be used to change the color properties of the polysaccharide covalently bound to them within great limits, and combinations of different dyes of general formula (I) can also achieve a specific coloration Basically, it can be used. By making at least one of the radicals R _{1 to} R ₈ an amino group, the dye can be further bonded to a plurality of functional groups in a particularly chemically simple manner. Thus, different viscoelastic polymers with corresponding different functional groups can also be quickly and easily coupled to the dyes of general formula (I) without the need for costly multi-step reactions, which provides a great cost advantage. Is brought about. All reactive dyes of general formula (I) exhibit a high extinction coefficient in the visible region of the light spectrum.

Furthermore, at least one polysaccharide can be obtained by reaction with at least one reactive dye of the general formula (II).

In the general formula (II), at least one of the substituents R _{1 to} R ₅ is an amino group, and at least one of the substituents R _{6 to} R ₁₀ is a nitro group. In this case, the remaining radicals R _{1 to} R ₁₀ different from the amino group and nitro group are hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -alkoxy-C _1-. C ₄ - _alkyl, C 1 -C ₄ - alkyl _-C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkoxy _-C 1 -C ₄ - alkoxy, aryloxy, acetamido, propionamido, butyramido, isobutyramide, From sulfonate, (aminophenyl) -N-alkylacetamide, (aminophenylsulfonyl) alkylsulfate, alkylbenzenesulfonamide, tri (alkyl) benzenamine, hydroxy, (alkylsulfonyl) benzeneamine, (alkenylsulfonyl) benzeneamine Select and / or at least 2 Adjacent substituents _{R y, R y + 1 (} y = 1~4 and / or 6-9) form a cyclic radical of the following,

In this case, R represents hydrogen, halogen, amino, hydroxyl, _nitro, C 1 -C ₄ alkyl _C 1 -C _{4 alkoxy,} C 1 -C ₄ - alkoxy _-C 1 -C ₄ - _alkyl, C 1 -C ₄ - alkyl _-C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkoxy - alkoxy _-C 1 -C _4. Here, all stereoisomers, racemic mixtures and positional isomers are considered to be included. With the dye of general formula (II), the color properties of the viscoelastic polymer covalently bound to it can also be varied within great limits, and different dye combinations of general formula (II) also achieve a specific coloration Therefore, it can be used basically. At least one of the radicals R _{1 to} R ₅ is an amino group and at least one of the radicals R _{6 to} R ₁₀ is a nitro group, resulting in a particularly high extinction coefficient in the visible region of the light spectrum. . Using at least one amino group, the dye can be further covalently linked to a plurality of functional groups by a particularly simple chemical method. Accordingly, various viscoelastic polymers with various corresponding functional groups can also be quickly and easily coupled to the dyes of general formula (II) without the need for costly multi-step reactions, and are therefore very costly. Benefits are provided.

  In a further advantageous development of the invention, the at least one phenolic compound is a modified and / or unmodified hydroxycinnamic acid, phenylpropene, coumarin, hydroxycoumarin, isocoumarin, chromone, hydroxybenzoic acid, in particular salicylic acid and acetylsalicylic acid, Tocopherol, tocotrienol, propofol, phenolic acid, phenolaldehyde, N- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl) -4- (3- Methoxyphenyl) -1-piperazineacetamide, butylhydroxyanisole, butylhydroxytoluene, galvinoxyl, benzoquinone, acetophenone, tyrosine derivative, phenylacetic acid, naphthoquinone, xanthonoid, stilbenoid Resveratrol, anthraquinone, flavonol, dihydroflavonol, tannin, pseudotannin, anthocyanin, anthocyanidin, flavanol monomer, especially catechin, flavanol polymer, especially proanthocyanidin, flavanone, flavone, carconoid, isoflavonoid, neoflavonoid, lignan , Neolignan, biflavonoids, catechol melanin, flavoranes, theaflavins and thealvidin. In this way, the radical scavenging properties, viscoelastic properties, and finally the coloration of the ophthalmic viscoelastic device can be adjusted to be optimal for each purpose of application.

  Modified and / or unmodified hydroxycinnamic acids are, for example, 3-caffeoylquinic acid, 3-p-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-feruloylquinic acid. P-coumaroyl glucose, feruloyl glucose, caffeic acid-4-O-flucoside, p-coumaric acid-O-glucoside and feruloyl acid-O-glucoside.

  The term modified and / or unmodified coumarin or hydroxycoumarin is intended to indicate, for example, coumarin, umbelliferone, hernialine, esculetin, scopoletin and flaxetine.

  Modified and / or unmodified phenolic acid and hydroxybenzoic acid are, for example, phenolic acid, hydroxycinnamic acid, coumaric acid, ferulic acid, caffeic acid, sinapinic acid, gallic acid, salicylic acid, acetylsalicylic acid, 4-hydroxybenzoic acid, It will be understood that they are 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, 3-methoxy-4-hydroxybenzoic acid and ellagic acid.

Tocopherols include in particular alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol. Tocopherol and tocotrienol are fat-soluble antioxidants. OVD can also be advantageously used in aqueous solutions by covalently bonding one or more of these compounds to a viscoelastic polymer.

  Suitable stilbenoids that exhibit particularly good scavenger properties include aglycone piceatannol, pinosylvin, pterostilbene and resveratrol.

  Tannin is a plant-derived polyphenol compound and has a molecular weight of 500 to 3,000 (gallic acid ester) or more and 20,000 (proanthocyanidins) g / mol or less. There are three main classes of tannins. The basic unit of the first class consists of gallic acid, the basic unit of the second class consists of flavones, and the basic unit of the third class consists of phloroglucinol. Pseudotannin is a low molecular weight compound that associates with other compounds. Tannins and pseudotannins exhibit good antioxidant properties.

  The terms modified and / or unmodified flavanol monomers and flavanol polymers refer in particular to catechins such as catechin, epicatechin, gallocatechin, epigallocatechin, proanthocyanidins and prodelphinidins. Proanthocyanidins and prodelphinidins are colorless precursors of anthocyanidins. In harsh environments, carbocations can be generated from proanthocyanidins and prodelphinidins. Carbocations are formed, for example, to form colored anthocyanidins or anthocyanidins in the presence of oxygen.

  Anthocyanins and anthocyanidins, which are flavilium cation derivatives of anthocyanins, turn red, purple, blue or yellow depending on the pH. That is, by covalently bonding the viscoelastic polymer with a phenolic compound from the group of anthocyanins and / or anthocyanidins, the ophthalmic viscoelastic device can have scavenger properties and pH dependent color properties. Accordingly, ophthalmic viscoelastic devices are easy to handle and can be advantageously used to easily detect or display normal or abnormal pH values in ocular tissue. Anthocyanidins include, for example, aurantidine, cyanidin, delphinidin, europinidine, luteolinidine, pelargonidin, malvidin, peonidin, petunidin and rosinidine.

  Flavanones and flavones are a class of flavonoids based on the 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) skeleton and exhibit particularly good scavenger properties. Furthermore, flavones have the additional advantage that they are colored compounds. Flavonones that can be used in connection with the present invention include, for example, apigenin, acacetin, luteolin, chrysin, chrysoeriol, diosmethine, tectocricin, scutellarein, oipatrin, genquanine, sinensetin and ougonine. Synthetic flavones include, for example, 4'-amino-6-hydroxyflavone, diosmin and flavoxate.

  Suitable theaflavins for use in the present invention include, for example, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3-3'-digallate. Still further, thearuvidin can be used, which are mostly high molecular weight polyphenols formed during the enzymatic oxidation of tea leaves. Thealvidin is usually red.

  In a further advantageous development of the invention, at least one phenolic compound is glycosylated. Glycosylation is a reaction that binds a carbohydrate to the hydroxyl or other functional group of a phenolic compound that acts as a glycosyl acceptor. Glycosylation plays a variety of structural and functional roles and can be used, among other things, to affect the viscoelastic properties of viscoelastic polymers and the biological resistance of viscoelastic polymers. Examples of glycosylated phenol compounds include Cy-3-gal, Cy-3-ara, Cy-7-ara, Cy-3-gal, Cy-3-glc, Cy-3-glc, Cy-3. -Rut, Peo-3-glc, Peo-3-rut, Cy-3-sop, Cy-3-glc-rut, Pg-3-glc, Pg-3-gal, Cy-3-glc, Pet-3 -Gly, Del-3-glc, Del-3-gal, Mv-3-glc, Cy-3-glc-sop, Cy-3-xyl-rut, Cy-3-sam, Mv-3, 5-diglc , Mv-3-p-cumaroylglc-5-glc, Mv-3-p-caffeoylglc-5-glc, Peo-3-p-cumaroylglc-5-glc or Del-3-glc-glc Any anthocyanins, Cy = cyanidine, Del = delphinidin, Mv = malvidin, Peo = peonidin, Pet = petunidin, Pg = pelargonidin, ara = arabinoside, gal = galactoside, glc = glucoside, gly = glycoside, ut = lutinoside, sam = Sambubioside, sop = sophoroside, xyl = xyloside, glc-rut = glucosyl rutinoside.

  Further advantages are from 20,000 to 8,000,000 mPa.s. s, preferably 50,000 to 500,000 mPa.s. s. Is brought about by the zero shear viscosity of the ophthalmic viscoelastic device. Ophthalmic viscoelastic devices thereby have a particularly good flow behavior and are accordingly easier to handle in typical applications. Preferably, the ophthalmic viscoelastic device is an aqueous solution of a viscoelastic polymer that is covalently bonded to at least one phenolic compound.

  In a further advantageous development of the invention, the ophthalmic viscoelastic device is an aqueous ophthalmic solution that protects intraocular tissue in ophthalmic surgery, which solution comprises a viscoelastic polymer to which at least one phenolic compound is covalently bonded. It is out. Because of the integral, non-washable, and easily tunable scavenger properties of ophthalmic viscoelastic devices, OVD with aqueous solutions of viscoelastic polymers can be a risk of washing off phenolic compounds Can be introduced into the eye in a particularly simple and controlled manner without the risk of adversely affecting the tissue. All ophthalmic viscoelastic devices can be removed from the eye simply and safely, for example after a cataract surgery, without leaving. Ophthalmic viscoelastic devices can be prepared for use in ophthalmology, particularly in phacoemulsification.

  A second aspect of the invention relates to a method of manufacturing an ophthalmic viscoelastic device comprising at least one viscoelastic polymer, wherein at least one viscoelastic polymer is covalently bonded to at least one phenolic compound, Used as a component of viscoelastic devices. Covalent bonding of at least one phenolic compound with at least one viscoelastic polymer causes the phenolic compound acting as a free radical scavenger to diffuse into adjacent tissues, adversely affecting that tissue during use of the ophthalmic composition That will definitely disappear. This allows a substantially simple handling of the ophthalmic composition. In addition, the tissue is reliably protected from free radicals. In the simplest configuration, an ophthalmic viscoelastic device, which can also be referred to as an ophthalmic composition, is manufactured with a viscoelastic polymer covalently bonded to one type of phenolic compound. Alternatively, a plurality of different viscoelastic polymers and / or further additives can be used in the manufacture of ophthalmic viscoelastic devices. Regardless, two or more different phenolic compounds can be covalently bonded to the viscoelastic polymer, in which case the viscoelastic polysaccharide is optionally combined with other additives in the ophthalmic viscoelastic device. Used for manufacturing. Each suitable type of reaction that covalently bonds the phenolic compound to the viscoelastic polymer depends on the functional groups present in each case.

Conjugation between the viscoelastic polymer and the phenolic compound containing at least one free amino group can be obtained by reaction of the CNBr (cyanogen bromide) -activated polymer with the phenolic compound. Furthermore, an amino group-containing phenol compound is used and covalently bonded to the polysaccharide by an eel reaction. The Ugi reaction is a multi-component reaction involving ketones or aldehydes, amines, isocyanides and carboxylic acids. The product of the eel reaction is bisamide. The eel reaction is a non-catalytic reaction, but usually ends within a few minutes after the isocyanide addition. The main advantage of using the ugly reaction is the inherently high atom economy, since only water molecules are lost and the product yields are high. Thus, dyes containing amino groups can be coupled quickly, easily and in high yield with polymers containing keto, aldehyde and / or carboxylic acid functional groups. An example of a suitable viscoelastic polymer is hyaluronic acid. Hyaluronic acid is a polysaccharide having a repeating disaccharide unit of 3-N-acetylglucosamine and 4-glycoside bond linked by glucuronosyl-β-1, β-1, and the general formula is

It is.

  Still further, the so-called Williamson ether synthesis can be used, which is an organic reaction that forms an ether from an organic halide and an alcohol involving the reaction of a phenolate ion with a primary halide of a viscoelastic polymer. Still further, the binding reaction does not necessarily have to occur in the same medium. The binding reaction may occur at the interface between two phases of an immiscible solvent that includes a phenolic compound in one solvent phase and a viscoelastic polymer in the other solvent phase. This is known as an interfacial reaction in a two-phase system. However, the method according to the second aspect of the present invention is generally not limited to a particular synthesis route. Further advantages can be gathered from the description relating to the first aspect of the invention, in which case the advantageous embodiment of the first aspect of the invention is the preferred embodiment of the second aspect of the invention. Seen, and vice versa.

  In an advantageous development of the invention, to produce an ophthalmic viscoelastic device, a viscoelastic polymer and / or a physiologically acceptable salt thereof covalently bound to at least one phenolic compound is added to a buffer system and / or further It is dissolved and / or dispersed in a protic solvent, especially water, in an amount of 0.05 and 5 percent by weight with the drug and / or excipient. Within the scope of the present invention, amounts of 0.05 weight percent to 5 weight percent are in particular 0.05%, 0.15%, 0.25%, 0.35%, 0.45%,. 55%, 0.65%, 0.75%, 0.85%, 0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45%, 55%, 1.65%, 1.75%, 1.85%, 1.95%, 2.05%, 2.15%, 2.25%, 2.35%, 2.45%, 2. 55%, 2.65%, 2.75%, 2.85%, 2.95%, 3.05%, 3.15%, 3.25%, 3.35%, 3.45%, 3. 55%, 3.65%, 3.75%, 3.85%, 3.95%, 4.05%, 4.15%, 4.25%, 4.35%, 4.45%, 4.45% 55%, 4.65%, 4.75%, 4.85% It will be understood to be 4.95% and 5.00% and the corresponding intermediate value. Here, the characteristic profile of the ophthalmic composition can be optimally adapted for different application purposes.

  In a further advantageous development of the invention, the viscoelastic polymer and / or at least one phenolic compound is functionalized and covalently bonded via this added functional group in order to attach at least one phenolic compound. That is, first a functional group is introduced into the viscoelastic polymer, which is then reacted with at least one phenolic compound to covalently bond at least one phenolic compound to the polymer. In this way, at least one phenolic compound can be easily conjugated to different polymers having a corresponding specific functional group, which is largely independent of its precisely present reactive group. Alternatively or additionally, at least one phenolic compound can be first functionalized and then covalently linked to the viscoelastic polysaccharide via its newly generated functional group depending on the desired reaction type.

  In a further advantageous development of the invention, at least one phenolic compound is covalently bonded to the carboxyl group and / or the primary hydroxyl group of the elastic polymer. In the simplest method of covalently bonding a phenolic compound to a viscoelastic polymer, an esterification method is used. For example, the phenolic hydroxyl group of a phenolic compound (eg, hydroxyflavone) is esterified to the carboxyl group of a viscoelastic polymer (eg, hyaluronic acid) via an acid chloride or acid anhydride in the presence of potassium carbonate or pyridine. Can be combined by the Schotten-Baumann reaction. Preparation of esters includes, for example, the use of hyaluronic acid and alpha-tocopherol with vitamin A in mild conditions with trifluoroacetic anhydride as the catalytically active component. Still further, the phenolic compound can be coupled to the carboxyl group of the viscoelastic polymer by mild Steglich esterification using disynchylcarbodiimide (DCC) and 4- (dimethylamino) -pyridine (DMAP) as catalysts. Can do.

  In a further advantageous development of the invention, a viscoelastic polymer having a molecular weight of 500,000 u to 5,000,000 u, preferably 800,000 u to 2,500,000 u is covalently bonded to at least one phenolic compound. This also achieves particularly good flow behavior and thus good handling of the ophthalmic viscoelastic device. Furthermore, a plurality of phenol molecules can be covalently bonded to the above-mentioned viscoelastic polymer molecules having no molecular weight, which causes a great change in the viscoelastic properties of the polymer.

  A third aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to phycocyanin. Phycocyanin, together with allophycocyanin and phycoerythrin, is a chromoprotein complex derived from the light-collecting phycobiliprotein family. Phycocyanin is a characteristic light blue that absorbs orange and red light near 620 nm and emits fluorescence at about 650 nm. Allophycocyanin absorbs and emits light at a longer wavelength than phycocyanin C or phycocyanin R. Phycocyanin is contained in cyanobacteria. Phycobiliproteins have fluorescent properties and exhibit particularly good scavenger properties. A phycobiliprotein is composed of subunits having a protein backbone to which a linear tetrapyrrole chromophore is bound. Advantageous embodiments according to the first and second aspects of the invention are regarded as advantageous embodiments of the third embodiment of the invention and vice versa.

A fourth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to phycocyanobilin. Phycocyanobilin is a blue phycobilin, a tetrapyrrole chromophore contained in the chloroplasts of cyanobacteria and red algae, gray algae, and some crypto algae. Phycocyanobilin is present in the phycobiliproteins allophycocyanin and phycocyanin, which exhibit particularly good scavenger properties, which are energy acceptors. This is covalently attached to these phycobiliproteins by a thioether bond and has the following formula:

  Advantageous embodiments according to the first, second and third aspects are regarded as advantageous embodiments of the fourth embodiment of the invention and vice versa.

  A fifth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bound to carnitine. Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine and exhibits particularly good scavenger properties. Since it is widely used as a nutritional supplement, it is relatively inexpensive. There are two stereoisomers of carnitine: L-carnitine and D-carnitine. Advantageous embodiments according to the first, second, third and fourth aspects are regarded as advantageous embodiments of the fifth embodiment and vice versa.

  A sixth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to ambroxol. Ambroxol (trans-4- (2-amino-3,5-dibromobenzylamino) -cyclohexanol) is a viscous degradant used for the treatment of respiratory diseases associated with excessive epilepsy Are known. Surprisingly, it has been found that ambroxol also exhibits particularly good scavenger properties and can be used for the production of an ophthalmic viscoelastic device according to the invention. Advantageous embodiments according to the first, second, third, fourth and fifth aspects of the invention are regarded as advantageous embodiments of the sixth embodiment and vice versa.

  A seventh aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to deferoxamine. Deferoxamine, also known as desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB or desferal, is a bacterial siderophore produced by the radiogenus Streptomyces spirosus. This is known for medical use as a chelating agent used to remove excess iron from the body. DFO-B mesylate is commercially available. Surprisingly, it has been found that deferoxamine also exhibits particularly good scavenger properties and can be used for the production of an ophthalmic viscoelastic device according to the invention. Advantageous embodiments according to the first, second, third, fourth, fifth and sixth aspects of the invention are regarded as advantageous embodiments of the seventh aspect of the invention and vice versa.

  An eighth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to TEMPO and / or TEMPOL. TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl) oxyl, or (2,2,6,6-tetramethylpiperidin-1-yl) oxydanyl) and TEMPOL (4-hydroxy-tempo or 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a heterocyclic compound. Surprisingly, it has been found that TEMPO and TEMPOL also exhibit particularly good scavenger properties when bonded to viscoelastic polymers and can be used to produce ophthalmic viscoelastic devices according to the present invention. TEMPO / TEMPOL can be easily converted to, for example, hyaluronic acid via a carboxyl group by mild Steglich esterification using dicincyclohexylcarbodiimide (DCC) and 4- (dimethylamino) -pyridine (DMAP) as catalysts. Can be combined. Advantageous embodiments according to the first, second, third, fourth, fifth, sixth and seventh aspects of the invention are regarded as advantageous embodiments of the eighth aspect of the invention and vice versa. is there.

  A ninth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to carvedilol. Carvedilol ((±)-[3- (9H-carbazol-4-yloxy) -2-hydroxypropyl] [2- (2-methoxyphenoxy) ethyl] amine) is a treatment for mild to severe congestive heart failure It is known as a cardioselective β / α-1 blocker for use in medicine. Surprisingly, it has been found that carvedilol also exhibits particularly good scavenger properties and can be used for the production of ophthalmic viscoelastic devices according to the invention. Advantageous embodiments according to the first, second, third, fourth, fifth, sixth, seventh and eighth aspects of the invention are regarded as advantageous embodiments of the ninth aspect of the invention, The reverse is also true.

  A tenth aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bonded to gliclazide. Gliclazide (N- (hexahydrocyclopenta [c] pyrrol-2 (1H) -ylcarbonyl) -4-methylbenzenesulfonamide) is an oral hypoglycemic agent (antidiabetic) and is classified as a sulfonylurea. Surprisingly, it has been found that gliclazide also exhibits particularly good scavenger properties and can be used for the production of ophthalmic viscoelastic devices according to the invention. Advantageous embodiments according to the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth aspects of the present invention are advantageous embodiments of the tenth aspect of the present invention. And vice versa.

  An eleventh aspect of the invention relates to an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer. According to the present invention, at least one viscoelastic polymer is covalently bound to a compound that is compatible with the capture free radical. The standard method of creating a lens capsule for removing the opaque nucleus of the lens and inserting an artificial intraocular lens (IOL) is lens emulsification with a device that generates ultrasonic vibrations. Free radicals, peroxides, etc. are produced by these ultrasonic oscillations, which induce acoustic cavitation and cause water vapor dissociation. These free radicals are a major source of damage to the endothelium after cataract extraction by inducing apoptosis. The use of covalently attached scavengers removes or at least substantially reduces free radicals, thereby increasing the protective performance of OVD in addition to the viscoelastic properties of the polymer to which the scavenger is attached. In addition, the pH value and / or osmolality of the ophthalmic viscoelastic device may be adapted to reduce endothelial cell loss during cataract surgery. Advantageous embodiments according to the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth and tenth aspects of the invention are advantageous of the eleventh aspect of the invention. Considered as a preferred embodiment and vice versa.

  Further features of the invention will be apparent from the claims and the following embodiments. The above-described features and combinations of features and the features and feature combinations described in the following embodiments can be used not only in individual combinations but also in other combinations without departing from the spirit of the present invention.

  The present invention generally provides an ophthalmic viscoelastic device (OVD) comprising at least one viscoelastic polymer that is adapted for free radical scavenging or covalently attached to a compound capable of scavenging free radicals.

The standard method of creating a lens capsule for removing the opaque nucleus of the lens and inserting an artificial intraocular lens (IOL) is lens emulsification with a device that generates ultrasonic vibrations. The aligned cubic cell endothelial layer, particularly in the Descemet's membrane of the corneal endothelium, can be affected by this iatrogenic procedure. The endothelial cell layer maintains corneal transparency by regulating the net ion flux from the stroma to the aqueous humor that keeps the stroma relatively dehydrated. These cell densities in elderly cataract patients are approximately 2600 cells / mm ² . Corneal endothelial cells cannot divide and if their density drops to approximately 500 cells / mm ² , there is a risk of corneal edema due to stromal dehydration, and transparency cannot be maintained any more. This is one of the most serious complications often noted in early lens emulsification techniques. The delicate endothelial cell layer can be damaged, for example, by the generated hydroxyl radicals and the mechanical effects of the washing solution. Oxygen free radicals are generated by ultrasonic oscillation, which induces acoustic cavitation, which causes water vapor dissociation. These free radicals have been proposed to be a major source of endothelial damage after cataract extraction by inducing apoptosis. The endothelium can be protected by an ophthalmic viscoelastic device consisting of a viscoelastic polymer such as hydroxypropylmethylcellulose (HPMC), chondroitin sulfate or hyaluronic acid (HA). However, the use of scavengers that can reduce the amount of oxygen free radicals can greatly increase the protection of free radicals, thereby increasing the protective performance of OVD in addition to viscoelastic properties, suitable pH values and osmolality. Increases and decreases the loss of endothelial cells during cataract surgery.

  The combination of the OVD and the scavenger molecule by mixing or ionic bonding cannot safely prevent the scavenger molecule from dissociating from the OVD. However, diffusion into body fluids can cause unwanted local or global pharmacological effects by binding to receptor targets. The place where the scavengers work for tissue protection is the extracellular lumen of the anterior chamber. For example, when using a freely permeable permeable membrane tempol as a scavenger, this can penetrate adjacent cells.

  To ensure that such problems are avoided, radical scavenging activity is limited to where free radicals are generated by anchoring to OVD. Furthermore, low water solubility scavenger molecules can be used because aggregation is prevented by covalent bonds to the viscoelastic polymer, such as covalent bonds to the highly hydrophilic hyaluronic acid. Hydrophobic scavenger binding reduces the hydrophilicity of hyaluronic acid or other viscoelastic polymers only slightly.

  The amount of scavenger molecules per viscoelastic polymer molecule can be adjusted as needed to obtain appropriate rheological properties and optimal radical scavenging performance.

Hyaluronic acid is a viscoelastic polysaccharide having repetitive disaccharide units of glucuronosyl-β-1,3-N-acetylglucosamine linked by β-1,4-glycosidic bonds. The general formula is

It is.

  The carboxyl group or primary and secondary hydroxyl groups of hyaluronic acid should be used to covalently attach scavenger molecules to obtain OVD with further epithelial cell protection by removal of free radicals generated by lens emulsification of the lens. Can do.

  In the simplest configuration, a commercially available scavenger is preferably used. Preferably this is a functional group that can already be selectively attached to the viscoelastic polymer. Alternatively, scavenger molecules and / or viscoelastic polymers may be modified by introducing appropriate functional groups.

  The amount of free radicals generated during lens emulsification can be confirmed, for example, by electron spin resonance (ESR) spectroscopy. Scavenger molecules can react with these free radicals to form thermodynamically more stable radicals. For some capture molecules, such as the flavone phenolic class, this is possible by delocalizing non-functionally functioning electrons into an aromatic delocalized π-electron system. Therefore, the selected binding reaction must not interfere with the aromatic structural element because this impairs the capture activity.

Flavones share a common structural element (2-phenyl-4H-chromen-4-one) having the general formula:

Commercially available 4'-amino-6-hydroxyflavone (2- (4-aminophenyl) -6-hydroxy-4H-chromen-4-one) having the general formula

Can be covalently linked to the carboxyl group of hyaluronic acid (HA). The conjugation of HA and flavone can be obtained, for example, by the reaction of CNBr-active hyaluronic acid with visual diol and 4′-amino-6-hydroxyflavone, which has the following structure:

When using a phenol compound, for example,
(Apigenin),
(Luteolin), or
(Chrysin),
Such as hydroxy flavones, these phenolic hydroxyl groups by the so-called Schotten-Baumann reaction in the presence of potassium carbonate or pyridine, for example via the corresponding acid chlorides or acid anhydrides by the esterification reaction HA carboxyl Can be used to bond to a group. The resulting flavone-hyaluronic acid conjugate has the following structure:
(R = H, OH, OMe)

  It will be understood that when the phenolic compound contains multiple hydroxyl groups, various regioisomers can be formed by this reaction.

  The scavenger function can be further realized by covalently coupling α-tocopherol (vitamin E) and / or tempol with a viscoelastic polymer. A covalent bond to highly hydrophilic hyaluronic acid can produce a homogeneous OVD phase with free radical scavenging activity. However, the water solubility of fat-soluble α-tocopherol is less than 1 mg / l. Therefore, application of α-tocopherol to an aqueous solution of hyaluronic acid is less effective when covalently bonding α-tocopherol. However, the binding reaction need not necessarily occur within the same phase. A binding reaction may also occur at the interface between the two phases of an insoluble solution containing scavengers and hyaluronic acid in a particular solvent phase. This is known as an interfacial reaction in a two-phase system.

One possible method of preparing the ester bond between α-tocopherol and HA under mild conditions involves the use of trifluoroacetic anhydride, resulting in the following HA-tocopherol-conjugate:

Tempol can be synthesized by the following general reaction formula through hyaluronic acid via a carboxyl group by mild Steglich esterification using dicin cyclohexyl carbodiimide (DCC) and 4- (dimethylamino) -pyridine (DMAP) as catalysts. Can be combined.

The resulting HA-Tempol-conjugate has the general formula:

  Alternatively or additionally, other viscoelastic polymers such as, for example, hydroxypropylmethylcellulose, chondroitin sulfate or mixtures thereof can basically be used for hyaluronic acid.

  In ophthalmic surgery, the OVD according to the present invention may be used for anterior segment surgery, especially for filling the vitreous during cataract surgery and for stabilizing the anterior chamber and protecting the sensitive endothelial cell layer of the cornea. it can. For example, hyaluronic acid is suitable as a viscoelastic polymer for covalently binding the dye / scavenger.

A further example relates to OVD comprising at least one viscoelastic polymer, wherein at least one viscoelastic polymer is covalently bonded to at least one scavenger, such as a phenolic compound, and further covalently bonded to at least one dye. Suitable dyes that can be covalently attached to hyaluronic acid or another polysaccharide are based on aminoanthracenedione induction of the following general formula (I):

In this formula (I), at least one of the substituents R _{1 to} R ₈ is an amino group, and the remaining substituents R _{1 to} R ₈ different from the amino group are hydrogen, halogen, C ₁ -C _{4 alkyl,} C 1 -C _{4 alkoxy,} C 1 -C ₄ - alkoxy _-C 1 -C ₄ - _alkyl, C 1 -C ₄ - alkyl _-C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkoxy - C ₁ -C ₄ -alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyramide, sulfonate, (aminophenyl) -N-alkylacetamide, (aminophenylsulfonyl) alkyl sulfate, alkylbenzenesulfonamide, tri ( Alkyl) benzeneamine, hydroxy, (alkylsulfonyl) benzeneamine and (alkenylsulfonyl) ) Selected from benzamine and / or in this formula, at least two adjacent substituents R _x , R _{x + 1} (x = 1-3 and / or 5-7) are 3-, 4-, 5-, Forms 6- or 7-membered monocyclic or heterocyclic, unsaturated or aromatic radicals.

Alternatively or additionally, the following general formula (II):

Reactive dyes from the group of ((nitrophenyl) diazenyl) benzenamine derivatives having the following may be covalently attached to the polysaccharide, in which case in formula (II) at least _one of the substituents R _{1 to} R ₅ One is an amino group and at least one of the substituents R _{6 to} R ₁₀ is a nitro group, and in this case, the remaining radicals R _{1 to} R ₁₀ different from the amino group and the nitro group are hydrogenated. _halogen, C 1 -C _{4 alkyl,} C 1 -C _{4 alkoxy,} C 1 -C ₄ - alkoxy _-C 1 -C ₄ - _alkyl, C 1 -C ₄ - alkyl _-C 1 -C ₄ - alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyramide, sulfonate, (aminophenyl) Selected from -N-alkylacetamides, (aminophenylsulfonyl) alkyl sulfates, alkylbenzenesulfonamides, tri (alkyl) benzenamines, hydroxy, (alkylsulfonyl) benzenamines and (alkenylsulfonyl) benzazeamines and / or of this formula Wherein at least two adjacent substituents R _y , R _{y + 1} (y = 1 to 4 and / or 6 to 9) are cyclic radicals:

Form, in which case, R represents hydrogen, halogen, amino, hydroxyl, _nitro, C 1 -C _{4 alkyl,} C 1 -C _{4 alkoxy,} C 1 -C ₄ - alkoxy _-C 1 -C ₄ - alkyl, C ₁ -C ₄ - alkyl _-C 1 -C ₄ - alkoxy and / or _C 1 -C ₄ - alkoxy _-C 1 -C ₄ - alkoxy.

Since both the dyes of the general formula (I) and the dyes of the general formula (II) have a free amino group, these can be obtained by a so-called Ugi reaction with a polysaccharide having a free keto group, an aldehyde group and / or a carboxyl group. Coupling can be done without further derivatization or functionalization. The Ugi reaction is a four-component condensation (U-4CC), which allows the synthesis of α-aminoacylamide derivatives from aldehydes, amines, carboxylic acids and isocyanides. In this case, the eel reaction proceeds by a general reaction scheme:

  Thus, in certain cases, the dyes / scavengers of general formulas (I) and (II) function as the amino component and hyaluronic acid functions as the carboxylic acid component of the ogi reaction. For example, acetaldehyde can be used as an aldehyde. For example, cyclohexanenitrile is suitable as an isocyanide. In general, low molecular weight alcohol has a proven record as a solution for the eel reaction.

  Preferably, the reaction is prepared at high concentration by cooling and allowed to react in a very short period of time within a few minutes at room temperature. Lewis acids, which are known per se, can be used in the conversion of sterically bulky educts for catalytic reactions.

For hyaluronic acid having the general formula:

The dyes of the general formulas (I) and (II) can therefore react with the free carboxyl group of hyaluronic acid using their amino group in the reaction stage, and can thereby be covalently bound to hyaluronic acid. Carboxylic acids used within the scope of the eel reaction can be advantageously varied so that other polysaccharides with free carboxyl groups can also be used within the scope of the eel reaction without prior functionalization. Can be changed. Polysaccharides that do not contain a carboxyl group can be derivatized or functionalized before for later use in the Ugi reaction. Conversely, free amino group-containing polysaccharides can of course also be reacted with dyes containing free carboxyl groups.

  The advantage of the dyes of the general formulas (I) and (II) is basically a very high extinction coefficient in the visible region (about 400 nm to about 800 nm) of the light spectrum. Furthermore, the color of the dyes of the general formulas (I) and (II) can be easily varied in a wide range of colors by using the corresponding substituents and / or regioisomers, thereby varying the ophthalmic composition It can be easily adapted to the intended use.

  In Table 1 below, various embodiments of the dye of general formula (I) are identified.

  In Table 2 below, various embodiments of the dye of general formula (II) are identified.

  However, in addition to the eel reaction, basically other chemical reaction types can also be used for the covalent attachment of the dye and / or the scavenger compound to the viscoelastic polymer. For example, a free alcohol group-containing dye such as a phenol compound can be bound to hyaluronic acid by an esterification reaction.

The labeling of hyaluronic acid (HA) can be performed, for example, by reacting CNBr-activated HA in a neighboring diol with a reactive amine group-containing dye according to the following reaction scheme:
In this case, HA represents hyaluronic acid, and NH ₂ —R represents a reactive dye containing an amine group. This reaction may involve a hydroxyl group in the two hyaluronic acid molecules.

Using a dye containing a phenolic compound and / or an additional scavenger molecule and / or an isothiocyanate group (represented by SCN-R) which primarily targets the primary hydroxyl groups or other viscoelastic polysaccharides of HA You can also.

  The reaction is carried out overnight at 37 ° C. The resulting color-labeled polysaccharide is stable for several months.

An additional reaction type that covalently bonds the dye to hyaluronic acid is the activation of hyaluronic acid derivatives by N-hydroxysuccinimide-linked diphenyl phosphate. The resulting adduct is reacted with a reactive hydrazide group-containing dye (represented by [R] CC (NN) = 0) according to the following general reaction scheme:

Another method of chemically coupling reactive dyes with hyaluronic acid (HA) or other polysaccharides containing carboxyl groups is represented by the following reaction scheme:

In this reaction, a hydrazide group-containing dye is used. In the first step, an O-acyl urea of HA having the following formula is formed by reaction of HA with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC).

  The resulting intermediate is then reacted with a reactive dye to form a color labeled HA.

Another method is to react the carboxyl group of HA with a carbodiimide group-containing dye with or without a primary amine at pH 4.5 according to a general reaction scheme:

  The reaction of carbodiimide proceeds rapidly at room temperature. The final group is N-acyl urea or O-acyl urea. Carbodiimide is a two-step reaction, ie, a reaction in which thiourea is formed by reacting a primary amine-containing dye and isothiocyanic acid, and a reaction in which this thiourea and HgO are reacted to form a carbodiimide group-containing reactive dye. And synthesized.

HA esters can also be prepared by nucleophilic reaction of halide-containing reactive dyes with quaternary salts of hyaluronic acid:

Another method for molecularly labeling viscoelastic polysaccharides is by reaction of HA with diepoxy.

  In the acidic state, the HA ester is formed by bonding the epoxy to the HA at the acid position. Under basic conditions, ethers are prepared by bonding an epoxy to HA at the primary alcohol position.

Another method of functionalizing HA at the primary alcohol position involves the use of divinyl sulfone:

  Alternatively, in this case, a free hydroxy group-containing dye can be used and bonded to hyaluronic acid using a crosslinking agent.

  Alternatively or additionally, hyaluronic acid can basically also use other viscoelastic polymers, in particular polysaccharides such as, for example, hydroxypropylmethylcellulose, chondroitin sulfate or mixtures thereof.

  OVD (or ophthalmic composition) comprising an aqueous solution of a viscoelastic polysaccharide covalently bound to a scavenger compound and further containing some dyes of general formula (I) and / or (II) is used in the method of lens emulsification can do. During lens emulsification, the anterior chamber of the eye is filled with an ophthalmic composition containing a colored viscoelastic solution. Viscoelastic OVD simplifies intraocular manipulation during lens emulsification, as a surgical tool to protect intraocular tissues such as corneal endothelium, and to keep the anterior chamber of the eye, for example, to perform a controlled capsulotomy It is used as a space retention agent. Since the scavenger and dye are covalently bonded to the viscoelastic polymer, the scavenger and dye do not diffuse out of solution and thus do not adversely affect or contaminate the surrounding tissue.

  Since the surgeon can visualize even very small traces of colored viscoelastic polymer, the colored OVD can be completely removed from the anterior chamber after capsulotomy.

Claims (15)

An ophthalmic viscoelastic device comprising at least one viscoelastic polymer comprising:
The at least one viscoelastic polymer is covalently bonded to at least one phenolic compound, and the at least one viscoelastic polymer is covalently bonded to at least one dye;
The dye is
Phenolic compounds, and / or
Reactive dyes from the group of modified and / or unmodified nitrophenyldiazenylbenzenamines,
The ophthalmic viscoelastic device is an aqueous ophthalmic solution that protects intraocular tissue in ophthalmic surgery, the aqueous ophthalmic solution comprising the viscoelastic polymer to which the at least one phenolic compound is covalently bonded;
An ophthalmic viscoelastic device characterized by that.   2. The ophthalmic viscoelastic device according to claim 1, wherein the at least one phenol compound is bonded to the viscoelastic polymer directly and / or via a spacer.   3. The ophthalmic viscoelastic device according to claim 1 or 2, wherein the viscoelastic polymer contains a polysaccharide.   The ophthalmic viscoelastic device according to claim 3, wherein the polysaccharide is cellulose ether having a cellulose, methyl and / or ethyl and / or propyl group, glycosaminoglycan, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid. An ophthalmic viscoelastic device, characterized in that it is amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan and / or a mixture thereof. The ophthalmic viscoelastic device according to claim 4,
The cellulose ether having a methyl and / or ethyl and / or propyl group is hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and / or methylcellulose;
The glycosaminoglycan is hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and / or keratan sulfate.
An ophthalmic viscoelastic device characterized by that.   The ophthalmic viscoelastic device according to any one of claims 1 to 5, wherein the at least one phenolic compound is modified and / or unmodified hydroxycinnamic acid, hydroxycoumarin, hydroxybenzoic acid, tocopherol, tocotrienol, propofol. , Phenolic acid, phenolaldehyde, N- (2,3-dihydro-7-hydroxy-2,2,4,6-tetramethyl-1H-inden-1-yl) -4- (3-methoxyphenyl) -1 -Piperazine acetamide, butylhydroxyanisole, butylhydroxytoluene, tyrosine derivatives, phenylacetic acid, naphthoquinone, xanthonoids, stilbenoids, anthraquinones, flavonols, dihydroflavonols, tannins, pseudotannins, anthocyanins, anthocyanins Ophthalmic viscoelastic device characterized by being selected from the group consisting of flavanol monomers, flavanol polymers, flavanones, flavones, carconoids, isoflavonoids, neoflavonoids, lignans, neolignans, biflavonoids, catechol melanin, flavoranes, theaflavins and thealvidin . The ophthalmic viscoelastic device according to claim 6,
The hydroxybenzoic acid is salicylic acid and / or acetylsalicylic acid;
The stilbenoid is resveratrol,
The flavanol monomer is catechin,
The flavanol polymer is proanthocyanidins;
An ophthalmic viscoelastic device characterized by that.   The ophthalmic viscoelastic device according to any one of claims 1 to 7, wherein the at least one phenol compound is glycosylated.   The ophthalmic viscoelastic device according to any one of claims 1 to 8, wherein the ophthalmic viscoelastic device has a zero shear viscosity of 20,000 to 8,000,000 mPa.s. s, preferably 50,000 to 500,000 mPa.s. An ophthalmic viscoelastic device characterized by being s. A method of manufacturing an ophthalmic viscoelastic device comprising at least one viscoelastic polymer comprising:
Covalently bonding the at least one viscoelastic polymer to at least one phenolic compound, and further covalently bonding the at least one viscoelastic polymer to at least one dye;
The dye is
Phenolic compounds, and / or
Reactive dyes from the group of modified and / or unmodified nitrophenyldiazenylbenzenamines,
The ophthalmic viscoelastic device is an aqueous ophthalmic solution that protects intraocular tissue in ophthalmic surgery;
A method wherein the at least one viscoelastic polymer is used as a component of the ophthalmic viscoelastic device.   11. The method according to claim 10, wherein for producing the ophthalmic viscoelastic device, the viscoelastic polymer and / or physiologically acceptable salt thereof covalently bonded to the at least one phenolic compound is incorporated into a buffer system and / or further A method comprising dissolving and / or dispersing in a protic solvent with an agent and / or excipient in an amount of 0.05 weight percent to 5 weight percent.   The method of claim 11, wherein the protic solvent is water.   13. The method according to any one of claims 10 to 12, wherein the viscoelastic polymer and / or the at least one phenol compound are functionalized to bind the at least one phenol compound via the additional functional group. A method characterized by covalent bonding.   14. The method according to any one of claims 10 to 13, wherein the at least one phenol compound is covalently bonded to a carboxyl group and / or a primary hydroxyl group of the viscoelastic polymer.   15. The method according to any one of claims 10 to 14, wherein the at least one viscoelastic polymer having a molecular weight of 500,000u to 5,000,000u, preferably 800,000u to 2,500,000u, is used. A method comprising covalently bonding to a phenol compound.